ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6481C>T (p.Arg2161Cys) (rs1064793958)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483842 SCV000567452 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.6481C>T at the cDNA level, p.Arg2161Cys (R2161C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2161Cys was not observed in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg2161Cys is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Arg2161Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000688167 SCV000815769 uncertain significance Ataxia-telangiectasia syndrome 2018-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2161 of the ATM protein (p.Arg2161Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 419565). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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